title: Nesfatin-1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats.
abstract: Nesfatin-1, a peptide whose receptor is yet to be identified, has been involved in the modulation of feeding, stress, and metabolic responses. More recently, increasing evidence supports a modulatory role for nesfatin-1 in autonomic and cardiovascular activity. This study was undertaken to test if the expression of nesfatin-1 in the nucleus ambiguus, a key site for parasympathetic cardiac control, may be correlated with a functional role. As we have previously demonstrated that nesfatin-1 elicits Ca²⁺ signaling in hypothalamic neurons, we first assessed the effect of this peptide on cytosolic Ca²⁺ in cardiac pre-ganglionic neurons of nucleus ambiguus. We provide evidence that nesfatin-1 increases cytosolic Ca²⁺ concentration via a Gi/o-coupled mechanism. The nesfatin-1-induced Ca²⁺ rise is critically dependent on Ca²⁺ influx via P/Q-type voltage-activated Ca²⁺ channels. Repeated administration of nesfatin-1 leads to tachyphylaxis. Furthermore, nesfatin-1 produces a dose-dependent depolarization of cardiac vagal neurons via a Gi/o-coupled mechanism. In vivo studies, using telemetric and tail-cuff monitoring of heart rate and blood pressure, indicate that microinjection of nesfatin-1 into the nucleus ambiguus produces bradycardia not accompanied by a change in blood pressure in conscious rats. Taken together, our results identify for the first time that nesfatin-1 decreases heart rate by activating cardiac vagal neurons of nucleus ambiguus. Our results indicate that nesfatin-1, one of the most potent feeding peptides, increases cytosolic Ca²⁺ by promoting Ca²⁺ influx via P/Q channels and depolarizes nucleus ambiguus neurons; both effects are Gi/o-mediated. In vivo studies indicate that microinjection of nesfatin-1 into nucleus ambiguus produces bradycardia in conscious rats. This is the first report that nesfatin-1 increases the parasympathetic cardiac tone.
authors.affiliation: Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, Pennsylvania, USA.
authors.forename: G Cristina
authors.initials: GC
authors.lastname: Brailoiu
authors.forename: Elena
authors.initials: E
authors.lastname: Deliu
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Tica
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rabinowitz
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.forename: Khalid
authors.initials: K
authors.lastname: Benamar
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020865:Calcium Channels, P-Type / Q000187:drug effects; D020907:Calcium Channels, Q-Type / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D000080866:Nucleobindins; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D013618:Tachyphylaxis / Q000502:physiology; D013686:Telemetry; D014630:Vagus Nerve / Q000166:cytology / Q000187:drug effects*
chemical_list: D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C000630652:Nucb1 protein, rat; D000080866:Nucleobindins; D043562:Receptors, G-Protein-Coupled; D002118:Calcium
keywords: autonomic control; calcium imaging; cardio-vascular regulation